title: Discovery of bufadienolides as a novel class of ClC-3 chloride channel activators with antitumor activities.
abstract: ClC-3 chloride (Cl(-)) channel has been shown to be involved in cell proliferation, cell cycle, and cell migration processes. Herein, we found that a series of bufadienolides isolated from toad venom were a novel class of ClC-3 Cl(-) channel activators with antitumor activities. Bufalin, which has the most potent antitumor activity, and 15β-acetyloxybufalin, which has no antitumor activity, were chosen as representative compounds to investigate the role of the ClC-3 Cl(-) channel. It was found that bufalin rapidly elicited activation of the ClC-3 Cl(-) channel and subsequently induced apoptosis through inhibition of the PI3K/Akt/mTOR pathway. The PI3K/Akt/mTOR pathway was attenuated by pretreatment with Cl(-) channel blockers [tamoxifen and 5-nitro-2-(3-phenylpropylamino)benzoic acid, NPPB] or ClC-3 small interfereing RNA. In summary, we discovered that activation of the ClC-3 Cl(-) channel, which subsequently induced inhibition of the PI3K/Akt/mTOR signaling pathway, was involved in the antitumor activities of bufadienolides.
authors.affiliation: College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research and §Department of Pharmacology, College of Medicine, Jinan University , Guangzhou 510632, People's Republic of China.
authors.forename: Junshan
authors.initials: J
authors.lastname: Liu
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Ruan
authors.forename: Lijuan
authors.initials: L
authors.lastname: Deng
authors.forename: Liwei
authors.initials: L
authors.lastname: Wang
authors.forename: Haiyan
authors.initials: H
authors.lastname: Tian
authors.forename: Anita
authors.initials: A
authors.lastname: Yiu
authors.forename: Chunlin
authors.initials: C
authors.lastname: Fan
authors.forename: Hai
authors.initials: H
authors.lastname: Luo
authors.forename: Shanwen
authors.initials: S
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Gaokeng
authors.initials: G
authors.lastname: Xiao
authors.forename: Lixin
authors.initials: L
authors.lastname: Chen
authors.forename: Wencai
authors.initials: W
authors.lastname: Ye
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002018:Bufanolides / Q000494:pharmacology*; D018118:Chloride Channels / Q000187:drug effects*; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D018118:Chloride Channels; C115376:ClC-3 channel; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000254:Sodium-Potassium-Exchanging ATPase